3-substituted derivatives or 1,3(3h)-benzoxazine-2,4-dione

ABSTRACT

COMPOUNDS WHICH ARE A SERIES OF 3-SUBSTITUTED DERIVATIVES OF 1,3(3H)-BENZOXAZINE-2,4-DIONE THAT ARE USEFUL AS ANALGETIC AGENTS. THESE COMPOUNDS ARE PREPARED BY REACTING AN APPROPRIATE N-SUBSTITUTED SALICYLAMIDE DERIVATIVE WITH A RING CLOSING AGENT.

3,751,414 3-SUBSTITUTED DERIVATIVES R 1,3(3H)- BENZOXAZINE-2,4-DIONEHerbert John Havera, Edwardsburg, Mich., and Shin Hayao, Tokyo, Japan,assignors to Miles Laboratories, Inc., Elkhart, Ind.

No Drawing. Continuation-impart of abandoned application Ser. No.563,959, July 11, 1966. This application Sept. 13, 1971, Ser. No.180,092

Int. Cl. C07d 87/10 US. Cl. 260244 R 4 Claims ABSTRACT OF THE DISCLOSURECompounds which are a series of 3-substituted derivatives of1,3(3H)-benz0Xazine-2,4-dione that are useful as analgetic agents. Thesecompounds are prepared by reacting an appropriate N-substitutedsalicylamide derivative with a ring closing agent.

CROSS REFERENCES TO RELATED APPLICATIONS This application is acontinuation-in-part of US. patent application Ser. No. 653,959 filedJuly 11, 1966, now abandoned.

BACKGROUND OF THE INVENTION The invention relates to a novel series ofsubstituted 1,3(3H)-benzoxazine-2,4-diones in which the substituent isat the 3-position. The compounds of this invention can be represented bymeans of the following generic formula: formula:

where n is 2 or 3 and R represents a tertiary amino group. For example,R can be dialkylamino or polymethylene amino in which one of themethylene groups can be optionally replaced by a hetero atom such asoxygen or nitrogen and in which additionally one or more of themethylene groups can be substituted by alkyl, aryl, alkaryl, hydroxyl oralkoxyl groups. Such substitucnts as alkyl or aryl groups optionally canbe substituted with such groups as hydroxyl, alkyl, halogen or haloalkylradicals. For example, R can be or N in which X is a halogen. Such novelcompounds have unexpected pharmacological activity in that they elicit apotent analgetic response particularly when administered orally.

It is well recognized that few symptoms are more urgent than pain andthat few classes of drugs are more useful than analgetics that arecapable of safely, rapidly and conveniently alleviating such pain.Although there are a United States Patent 0 3,751,414 Patented Aug. 7,1973 ice large number of factors contributing to the cause of pain, manyof which are psychosomatic in origin, those skilled in the art haveaccepted methods of evaluating analgetic activity that yieldreproducible data. These methods have been described in detail in widelyavailable publications. Such evaluations have also been shown to yielddata that relates to a number of species of animals, not just thespecies being used in a model.

It is further recognized that a desirable analgetic should be effectedat a low dose such that a low total amount is required to obtain thedesired effect.

Also, a desirable analgetic should exhibit an increasing efiectivenesswith increasing dose. A medication demonstrating such a property isgenerally said to elicit a response which is dose dependent and topossess the observed pharmacological activity. This well-knowncharacteristic is set forth more fully, for example, in An Introductionto Pharmacology by Lewis, J. J. (1960), E. & S. Livingstone Ltd.; ThePharmacological Basis of Therapeutics, Goodman, L. S. and Gilman, A.,20, (1965), The MacMillan Co., 3rd Edition; and Phamacology andTherapeutics, Grollman, Arthur, (1965), Lea and Febiger, 6th Edition.

Potent analgetics are available that are capable of rapidly relievingsevere pain. However, these analgetics have generally been found toresult in an undesirable drug dependence when administered over periodsof time during which relief from such pain is required. These drugs havea further limitation in that they are substantially inactive, asanalgetics, when administered orally and, therefore, they must beadministered parenterally. This limitation on route of administrationalso results in a serious restriction in relation to such medicationssince special equipment and sanitary conditions are required for theiruse. Thus, it is difiicult, even when desirable, for a patient to treathimself with such analgetics.

Oral analgetics, such as acetaminophen and aspirin, although generallyeifective for minor pain, are not considered effective in the treatmentof more severe pain. When a dose large enough to relieve severe pain istaken, there may be many side reactions. Among these reactions arenausea, sedation, and other toxic side elfects.

Many compounds have been stated, in widely available publications, to beanalgetic agents, i.e. to elicit an analgetic response. However, areview of the most recently published list of acceptable analgeticagents appearing in Physicians Desk Reference 25th edition, 1971,clearly indicates that no new analgetics that are free of seriouscontraindications have become available in recent years.

Some closed ring compounds that have been stated to possess analgeticactivity, along with numerous other desirable pharmacologicalactivities, are those described in US. Pat. No. 3,122,538 having thestructural formula:

A compound of this group, 3-(2'-diethylaminoethyl)3,4-dihydro-2,4-dioxo-ZH-pyrido [2,3-e] 1,3 oxazine, having a threeposition substituent corresponding to one of the novel compounds of thisinvention was evaluated for analgetic activity according to theprocedure described by Bianchi, C. and Franceschini, J. in ExperimentalObservations on H-affners Method for Testing Analgesic Drugs, Brit. J.Pharmacol, 9:280 (1954). It 'Was observed that this compound did notelicit a true analgetic response when tested according to this acceptedmethod. The observed results of this evaluation are set forth in Table1.

TABLE 1 Percent failing to D mporid .A al a ED L 050 o s n o c DCompound Rte. mgJkg. stimulus tion mgJl g. w 50 i. 1.3-(2-diethylaminoethyl)3,4-dihydro-ZA-dioxmZH-pyrido[2,3-e](1,3)oxazine,"{Ll 2 ,3 2 3 Efgfff? i.p. 100 20 ----d0 C.N.S. stimulation: 0=none+=slight, ++=modorate, LD di n 1 th 1d 1 h mtensel the mama tsated-2aose) t at dose at w 1011 death occurs in 50% o 1 EDso (median effectivedose) that dose at which analgesia occurs in 50% of the individualstested.

Other closed ring compounds that have been stated to C H possessanalgetic activity, in addition to numerous other fi desirablepharmacological activities, are those described in v US. Pat. No.2,835,668 having the structural formula: 0,11,

A -N N -N k or -N \N- U R X CF:

in which X is a halogen, or acid addition salts thereof.

T 911 the compounds of this group, 3-[ "PY These compounds have usefulpharmacological activity. ethyl)]-1,3- benzoxazine 2,4 dionehydrochloride and For example, they display unexpected pharmacological'PY Y f f activity of a beneficial nature in that they have been foundchloride were evaluated for analgetic activity substantially to possesspotent analgetic activity Particularly these according to the abovestated procedure. It was observed pounds elicit a potent analgeticresponse when that the first stated compound did not elicit analgeticministered by the Sought after and advantageous oral activity whenadministered intraperitoneally or orally. route.

With this first compound substantial central nervous sys- DESCRIPTION OFTHE PREFERRED tem stimulation was observed. The second compound wasEMBODIMENTS observed to elicit an analgetic response when administeredintraperitoneally in spite of moderate central nervous The compounds ofthls mventlon can be y P system depression. However, when this lattercompound pared y e f PR P e N'substimted y was administered orally noanalgetic activity was obamlqe del'lvatlve Wlth e T1118 closlng f Suchagent served even up to doses (562.0 and 682.0 mg./kg.) at fumlshes acarbonyl group to close a Ilflg to form a which the test animals wentinto convulsions. Accordingly, benzoxaline dione derivative SucheOmPOHIIdS include it can be stated that these compounds do not meet thede- Phosgene, l y halofofmates y ha10eaIb( I1ateS- sirable characteristcof oral efficacy sought from a bene- The reaetlon be eonvemenfly earnedout 111 the ficial analgetic. The observed results for these compounds40 p e of a sultable Solvent PP as Xylene re s t forth i T bl 2,tonitrile. A base, for example, pyridine, can also be used TABLE 2Percent ailing to respond C.N.S. Dose, to stimula- Analgetlc ED LDN,Compound Rte. mgJkg. stimulus tion mgJkg. mgJkg. a-[2- g2pyridvlethyb]-1,3-bonzoxazine-2A-dione hydrochloride ikp. $3.; 53 +0 Notpbtalnable Do r i.p 68.2 5/20 D i.p 82.6 14 20 D i.p 100. 0 20/20 .0147.0 1/5 1 32 3.0 178.0 2/5 D p.o 215.0 4/5 D p.o 261.0 5/5 3-[2-(i-pyridylethyl)]-1,3-bnezoxazine-2A-dione hydrochloride Lp. 100. 0 2/10D l.p. 121. 0 6/10 D I i.p. 147. 0 9/10 D 5 a .0. 178.0 1/5 D: i 3.0.215.0 2 5 D p.o. 261.0 1/5 D p.o. 464.0 1/5 D p.o. 562.0 1/5 D p.o.682.0 1/5 NorE.See footnotes, Table 1.

SUMMARY OF THE INVENTION if desired. The process of preparation can beillustrated This invention is embodied in a series of compounds y meansof the following equation: having the following structural formula: 0 H

-N-CJm-R n 2n O =0 45 0 n InR in which C H is a straight chain alkylene,n is 2 or 3 =0 and R is 0 The compounds of this invention can beprepared in the form of their free bases or salts thereof. In additionvarious salts can be prepared by reaction with the appropriate acid.Although in general pharmacologically acceptable salts are preferred,other salts, even toxic salts, can be formed for use in purifying orseparating the compounds of this invention.

Medications may be prepared including at least one of the novelcompounds of this invention as an active ingredient in the form of thefree base or pharmacologically acceptable acid addition salt thereof.Such medications may be conveniently prepared by combining the activeingredient with a pharmaceutical vehicle including components selectedfrom the fillers, carriers, extenders, excipients, and the likegenerally used in pharmaceutical formulations. Medications may beprepared in the solid state as tablets or capsules or in the liquidstate as solutions or suspensions. Similar dosage forms suitable fororal, subcutaneous, intraperitoneal, or other convenient means ofadministration can also be provided. The pharmaceutical vehicle may alsoinclude common diluents or tableting adjuncts such as cellulose powder,cornstarch, lactose, talc and such, used according to acceptedpharmaceutical manufacturing practices. Unit dosages (a specific weight,such as mg. or g.) of active ingredient in a medication may be varied sothat an adequate amount is present to provide a desired therapeutic dosewithout untoward side efl ects. A therapeutic dose is considered as theratio of the weight of active ingredient administered to a patients bodyweight, usually expressed as mg./kg., that elicits a desired therapeuticresult.

This invention will be better understood by reference to the followingexamples which are not to be construed as limiting the scope of thisinvention which is defined in the claims appended hereto.

EXAMPLE 1 (A) 3-[3-(4-phenyl-1-piperazinyl)propyl]-1,3(3H)-benzoxazine-2,4-dione To 10.0 g. (0.029 mole) of4-phenyl-1-[3-(o-hydroxybenzamido)propyl]piperazine was added 100 ml. ofpyridine, 60 ml. of acetonitrile and 4.0 g. (0.03 mole) of ethylchlorocarbonate dropwise at 5 C. After the addition of ethylchlorocarbonate the mixture was distilled until the internal temperaturereached 122 C. The resulting solution was then refluxed for 1 hour.After cooling the mixture, water was added and a white precipitatefollowed. The solid was recrystallized two times from a chloroform,methanol solution. Yield 11.0 g., M.P. 126-128 C.

Analysis.--Calcd. for C H N O (percent): N (basic), 3.84; N (total),11.51. Found (percent): N (basic), 3.82; N (total), 11.60.

(B) 3-[3-(4-phenyl-1-piperazinyl)propyl]-1,3 (3H) benzoxazine-2,4-dionemaleate The maleate salt was prepared by adding 3.48 g. (0.03 mole) ofmaleic acid to the free base in methanol. The solution was heated on asteam bath for 15 minutes. .Upon cooling a precipitate formed which wasfiltered and recrystallized from a methanol, chloroform mixture. Yield10.0 g., M.P. 174-175 C.

Analysis.Calcd. for C25H27N307 (percent): N (basic), 2.91; N (total),8.73. Found (percent): N (basic), 2.88; N (total), 8.90.

EXAMPLE 2 (A) 3-[3-(4-m-chlorophenyl-1-piperazinyl)propyl]-1, 3 (3H)-benzoxazine-2,4-dione To 24.0 g. (0.07 mole) of4-m-chlorophenyl-1-[3-(o hydroxybenzamido)propyl]piperazine was added100 ml. of dry pyridine and 60 ml. of acetonitrile. To this solu- (B 3-3- 4-m-chlorophenyll-piperazinyl propyl] 1,3 (3H) -benzoxazine-2,4-dionemaleate The maleate salt was prepared by adding 2.32 g. (0.02 mole) ofmaleic acid to the 8.0 g. (0.02 mole) of free base in methanol. Themixture was heated on the steam bath for 15 minutes and then allowed tocool. A precipitate formed which was filtered and recrystallized from amethanol, chloroform solution twice. Yield 7.0 g., M.P. 172-l73 C.

Analysis.--Calcd. for C H CIN O (percent): N (hasic), 2.71; N (total),8.14. Found (percent): N (basic), 2.70; N (total), 8.03.

EXAMPLE 3 3-(2-diethylaminoethyl)-1,3 (3H)-benzoxazine-2-4- dionehydrochloride To 18.0 g. (0.076 mole) of diethylaminoethyl salicylamidewas added ml. of pyridine and 60 ml. of acetonitrile. To this solutionwas added 8.2 g. (0.076 mole) of ethyl chloroformate While keeping thetemperature at 5 C. After the addition of ethyl chloroformate themixture was distilled until the internal temperature was 122 C. At thispoint a solid precipitated from the reaction mixture. The material wasfiltered and recrystallized three times form a methanol, ether mixture.Yield 13.0 g., M.P. 232-233 C.

Analysis.-Calcd. for C H ClN O (percent): N (basic), 4.69; N (total),9.35. Found (percent): N (basic), 4.69; N (total), 9.33.

EXAMPLE 4 (A) 3- (3-morpholinopropyl) -1,3 (3H) -benzoxazine- 2,4-dioneTo 41.0 g. (0.15 mole) of 3-morpholinopropyl salicylamide was added 100ml. of dry pyridine and 60 ml. of acetonitrile. To this solution wasthen added 16.3 g. (0.15 mole) of ethyl chloroformate at 5 C. Theaddition was made so that the temperature never rose above 10 C. Themixture was then distilled until the internal temperature reached 122 C.The resulting solution was refluxed for an additional hour. Aftercooling, a solid precipitated which was filtered and treated with adilute ammonium hydroxide solution. The organic layer was extracted withchloroform and the chloroform was removed in vacuo leaving an oilyresidue. The oil crystallized upon addition of n-hexane. The solid wasrecrystallized three times from a chloroform, n-hexane mixture. Yield10.0 g., M.P. 88- 89 C.

Analysis.Calcd. for C H N O (percent): N (hasic), 4.83; N (total), 965.Found (percent): N (basic), 4.80; N (total), 9.81.

(B) 3-(3-morpholinopropyl)-1,3-(3H)-benzoxazine- 2,4-dione hydrochlorideThe hydrochloride salt was prepared by suspending the free base inmethanol and bubbling anhydrous hydrogen chloride through the mixture.The material which precipitated was recrystallized from a methanol,ether mixture. Yield 6.5 g., M.P. 227-228 C.

Analysis.Calcd. for C H ClN O (percent): N (basic), 4.28; N (total),8.57. Found (percent): N (basic), 4.26; N (total), 8.67.

7 EXAMPLE 3 [3 (4 m-trifluoromethylphenyl l piperazinyl) propyl] 1,3(3H) benzoxazine 2,4 dione hydro- 8 the root of the tail of each mousetested. The mouses attempts to remove the artery clip was observed andrecorded.

The observed results for i.p. and p.o. routes of adminischloride 5tration are set forth in Table 3.

TABLE 3 N0 failing Analto re- C.N.S. getie Dose, spond to stlmula- EDw,LDso, Compound Rte. mgJkg. stimulus tlon mg./kg. mgJkg.

3-(2-diethylaminoethyl)-1,3(3H)-benzoxazine-2,4-dione hydrochloride i.p.46.4 2/10 D0 i.p. 66.2 6/10 0 56.5 98 Do i.p. 68. 2 7/10 D0- i.p. 82.610/10 Do- 68. 2 2/ 10 0 Do... 82.6 6/10 0 84.6 225 Do 100.0 7/10 0 Do121.0 9/10 Norm-See footnotes, Table 1.

To 20.0 g. (0.05 mole) of 4-m-trifluoromethylphenyl-1- [3(o-hydroxybenzamido)propyl]piperazine was added 100 ml. of pyridine and60 ml. of acetonitrile. To this mixture was then added 5.4 g. (0.05mole) of ethyl chloroformate dropwise at 5 C. After the addition ofethyl chloroformate the mixture was distilled until the internaltemperature was 122 C. Approximately 120 ml. of distillate wascollected. The resulting solution was then refluxed for an additionalhour. The mixture was cooled and anhydrous ether was added toprecipitate the product. The solid was filtered and recrystallized fivetimes from a methanol, ether mixture. Yield 4.5 g., M.P. 231 233 C.

Andlysis.-Calcd. for C H ClF N O (percent): N (basic), 2.99; N (total),8.95. Found (percent): N (basic), 2.95; N (total), 8.84.

EXAMPLE 6 3- (2-diethylamiuoethyl) 1,3 (3H) -benzoxazine 2,4-dionehydrochloride To 0.2 g. of diethylaminoethyl salicylamide in 5 ml. ofxylene was added 100 mg. (0.00085 mole) of ethyl chloroformate. Themixture was heated to boiling and refluxed for minutes. The solid thatformed was filtered and recrystallized from a methanol, ether mixture.

Yield: 0.20 g. (77%), M.P. 231232 C.

Analysis.-Calcd. for C H ClN O (percent): N

(basic), 4.69; Found (percent): N (basic), 4.66.

EXAMPLES 7 AND 8 The analgesic activity of the novel compounds of thisinvention were evaluated substantially according to the proceduredescribed by Bianchi, C. and Franceschini, I. in ExperimentalObservations on Hafiners Method for Testing Analgesic Drugs Brit. J.Pharmacol, 9:280 (1954). A specific dose of the compound wasadministered to randomly selected mice. After minutes a noxious stimulusin the form of an artery clip with the branches enclosed in a thinrubber tube was applied to It was observed that this compound elicitedan analgetic response when administered by the i.p. and p.o. routes thatwas substantially free of adverse side effects. Further, it was observedthat the responses elicited was dose dependent for both routes ofadministration.

In summary this invention provides a series of 3-substituted derivativesof 1,3(3H)-benzoxazine-2,4-diones, which are useful as pharmacologicalagents.

What is claimed is:

1. A compound of the formula:

where C H is a straight chain alkylene in which n is 2 or 3 and R isReferences Cited UNITED STATES PATENTS 3,528,974 9/1970 Engel 260-244 R3,122,538 2/ 1964 Clauson-Kaas et a1. 260-244 R 2,835,668 5/ 1958Shapiro et al. 260244 R OTHER REFERENCES Ex parte Engel, available inUS. patent file 3,528,974,

Paper No. 18 (3 pages).

NATALIE TROUSOF, Primary Examiner US. Cl. X.R.

260--247.2 A, 248 Ph, 268 MK, 558 R; 424-248

